The overall goal of this application is to define the factors that shape antiviral T and B cell immunity and delineate the mechanisms by which these factors operate. We have focused on three factors that could shape effector and memory lymphocyte differentiation: i) co-infection and the associated inflammation, ii) tissue microenvironment, and iii) regulatory T cells (Treg). These inter-related topics were chosen because all have the potential to profoundly influence the quality and magnitude of antiviral T and B cell immunity and to have substantial impact on the design and application of antiviral vaccines or therapeutic interventions. A major gap in our understanding of antiviral immunity is how immune responses to a particular vaccine or infection are influenced by other ongoing immune responses. These other immune responses could be due to concomitant chronic infections, as is the case for nearly 2 billion people worldwide, due to secondary infections, as is often the case with respiratory viral infections, or simply due to a tissue microenvironment that has exposure to microbes or microbial products. The effect of these ongoing interactions with other microbes can likely vary from relative ignorance to robust local or systemic inflammatory responses. In essence, antiviral T and B cell responses do not develop in isolation from other ongoing immunological or inflammatory events, but there is little understanding of how bystander concomitant infections, inflammation or regulation impacts the development of optimal antiviral immunity. Addressing this question is the major focus of this application. RELEVANCE: The overall goal of this application is to define the factors that shape antiviral T and B cell immunity and delineate the mechanisms by which these factors operate. A better understanding of the factors that shape and regulate antiviral immunity should allow more effective vaccines and therapeutics to be developed. PROJECT 1: Regulation of altered memory CD8 T cell differentiation by co-infection (Wherry, J) PROJECT 1 DESCRIPTION (provided by applicant): The development of optimal T cell memory is the goal for many vaccination strategies for infectious disease. Yet the process of memory T cell differentiation and the factors that influence memory T cell quality remain poorly understood. Recent studies have highlighted a key role for inflammatory signals in regulating memory T cell differentiation with evidence indicating that inflammation can be beneficial for T cell priming, but can also induce terminal differentiation of effector T cells. Inflammation is a key feature of most infections, but it is unclear if the effects of unrelated infections can influence T cells of a different specificity in a setting of co-infection. Co-infection can have a negative effect on immunity to unrelated pathogens, but the immunological mechanisms for this effect are not known. In preliminary studies we have found that two types of chronic infections inhibit optimal generation of CD8 T cell memory to unrelated antigens. This effect was not due to persisting antigen since the specificity of the memory CD8 T cells examined was unrelated to the persisting infections. Thus, we hypothesize that the inflammatory environment of chronic infections can negatively impact the pattern of memory T cell differentiation. In this proposal we will test this hypothesis by examining the impact of the inflammatory environment on different subpopulations of effector and memory CD8 T cells and defining the molecular mechanisms for this effect. We will: 1) Determine which stages of memory CD8 T cell development are impacted by co-infection; 2) Define the pathways that regulate memory differentiation during co-infection; and 3) Define the transcriptional pathways controlling arrested memory T cell differentiation due to chronic co-infection. A better understanding of the impact of chronic co-infections on memory T cell differentiation is needed to help optimize antiviral vaccines. Our goal in this project is to begin to address these questions and investigate how bystander chronic infections shape antiviral memory T cell differentiation. RELEVANCE: More than 2 billion people worldwide are infected with HIV, HCV, HBV, malaria, TB and neglected tropical diseases. These same populations would benefit the most from improved vaccines. It is clear that chronic infections can impact immunity to unrelated antigens, but the immunological basis for this effect is unclear. Our goal is to define how unrelated infections impact immunological memory in hopes to improve vaccines.